Clinical Trials /

Stereotactic Body Radiotherapy (SBRT) Followed by Immunotherapy in Liver Cancer

NCT03203304

Description:

External beam photon stereotactic body radiotherapy (SBRT) using a linear accelerator to a total dose of 40 Gy in 5 fractions delivered once daily with at least 48 hours between each fraction. SBRT treatment will be completed within a 21-day window. Starting within 14 days after completion of SBRT, intravenous nivolumab 240 mg will be given every 2 weeks as monotherapy or in combination with ipilimumab 1 mg/kg IV every 6 weeks.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Stereotactic Body Radiotherapy (SBRT) Followed by Immunotherapy in Liver Cancer
  • Official Title: Phase I Study of Stereotactic Body Radiotherapy (SBRT) Followed by Nivolumab or Ipilimumab With Nivolumab in Unresectable Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: IRB17-0578
  • NCT ID: NCT03203304

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
NivolumabOpdivoNivolumab
IpilimumabYervoyNivolumab and ipilimumab

Purpose

External beam photon stereotactic body radiotherapy (SBRT) using a linear accelerator to a total dose of 40 Gy in 5 fractions delivered once daily with at least 48 hours between each fraction. SBRT treatment will be completed within a 21-day window. Starting within 14 days after completion of SBRT, intravenous nivolumab 240 mg will be given every 2 weeks as monotherapy or in combination with ipilimumab 1 mg/kg IV every 6 weeks.

Detailed Description

      1.1 Primary Objective & Hypothesis Determine the safety and tolerability of SBRT followed by
      nivolumab or ipilimumab with nivolumab for hepatocellular carcinoma by establishing the rates
      of toxicity that occur within 6 months from start of SBRT. Hypothesis: SBRT followed by
      nivolumab or nivolumab and ipilimumab will have similar toxicity to historical controls of
      SBRT or nivolumab monotherapy.

      1.2 Secondary Objectives and Hypotheses Estimate the investigator determined best overall
      response rate. Hypothesis: Combining radiation and nivolumab or nivolumab and ipilimumab will
      improve the best overall response rate compared to historical controls with SBRT or nivolumab
      alone.

      Estimate the rates of long-term adverse events (after 6 months) from the end of SBRT.
      Hypothesis: Long-term toxicity from SBRT with nivolumab or nivolumab and ipilimumab will be
      comparable to that observed with nivolumab monotherapy.

      Summarize the distant disease control, progression-free survival, and overall survival.
      Hypothesis: Disease control and survival will be comparable to (or better than) that observed
      with nivolumab monotherapy.

      Summarize the local control of the SBRT treated lesion. Hypothesis: Combining SBRT and
      nivolumab or nivolumab and ipilimumab will have similar (or better) local control rates as
      observed in SBRT only series.

      1.3 Exploratory Objectives Explore changes in inflammatory biomarkers (including, but not
      limited to CD8/Treg ratio, total CD4 counts, total lymphocyte count) in pretreatment and
      on-treatment serially collected peripheral blood samples. Hypothesis: Changes in inflammatory
      biomarkers after radiation therapy may correlate with a more favorable response to
      immunotherapy.

      Explore changes in the tumor microenvironment induced by radiation on pre and post treatment
      biopsies. Hypothesis: Changes in the tumor microenvironment after radiation therapy will be
      observed that may correlate with a more favorable response to immunotherapy.
    

Trial Arms

NameTypeDescriptionInterventions
NivolumabExperimentalPatients will be randomly placed in either of the two arms. All patients will undergo CT simulation and stereotactic body radiotherapy (SBRT). SBRT treatment will be completed within a 21-day window. After the final fraction of SBRT, patients will receive treatment with nivolumab 240 mg will be initiated within 14 days. Patients will receive nivolumab infusions once every 2 weeks. Patients will be restaged after every 4 doses of nivolumab (every 8 weeks). Treatment beyond progression is allowed as per irRC evaluation.
  • Nivolumab
Nivolumab and ipilimumabExperimentalPatients will be randomly placed in either of the two arms. All patients will undergo CT simulation and stereotactic body radiotherapy (SBRT). SBRT treatment will be completed within a 21-day window. After the final fraction of SBRT, treatment with nivolumab and ipilimumab will be initiated within 14 days. Patients will be restaged after every 4 doses of nivolumab (every 8 weeks). Treatment beyond progression will be allowed as per irRC evaluation. Patients will receive nivolumab infusions once every 2 weeks and ipilimumab infusions once every 6 weeks.
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent for the trial.

          -  Be ≥ 18 years of age on day of signing informed consent.

          -  Have ECOG performance status 0-1.

          -  Pretreatment CT chest /abdomen /pelvis within 28 days of protocol enrollment.

          -  Pathologic diagnosis of hepatocellular carcinoma (including fibrolamellar variants and
             biphenotypic tumors with an HCC component).

          -  Child Pugh Class A (score = 5 or 6)cirrhosis (assessed within 14 days of SBRT)

          -  Deemed ineligible for curative intent therapy with surgical resection or liver
             transplantation.

          -  Patients with diffuse/multifocal liver involvement are eligible.

          -  Patients with extrahepatic disease are eligible.

          -  Prior systemic therapies for HCC are allowed but not required.

          -  Must have at least one intrahepatic lesion amenable to SBRT.

          -  Prior transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) allowed,
             however, patient must have separate intrahepatic lesion amenable to SBRT and biopsy.

          -  Intrahepatic lesion amenable to pre and post SBRT biopsies, unless the investigator
             determines that the tumor biopsies would be unsafe.

          -  Have measurable disease based on RECIST 1.1.

          -  Demonstrate adequate organ function as defined in Table 1. All screening labs should
             be performed within 14 days of treatment initiation.

        Table 1 - Adequate Organ Function Laboratory Values System Laboratory Value Hematological
        Platelets ≥ 40,000 / mcL Hepatic Serum total bilirubin ≤ 3 mg/dL AST (SGOT) and ALT (SGPT)
        ≤ 5 X ULN

          -  Negative urine or serum pregnancy within 72 hours prior to receiving the first dose of
             study medication for female subjects of childbearing age.

          -  Subjects should agree to use an adequate method of contraception starting with the
             first dose of study therapy through 150 days after the last dose of study therapy (for
             women of child-bearing potential) or 210 days after the last dose of study therapy
             (for men who have partners of child-bearing potential).

          -  Have a life expectancy of greater than 6 months (in the opinion of the treating
             physician).

        Exclusion Criteria:

          -  Prior external beam radiation therapy to the liver (defined as > 1 Gy).

          -  Prior yttrium-90 radioembolization treatment.

          -  Patients with HBV viral load > 100 IU/mL (antiviral therapy per local practice is
             required).

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose
             of >10 mg prednisone daily or equivalent at time of first dose of trial treatment.

          -  Has a known history of active TB (Bacillus Tuberculosis).

          -  Hypersensitivity to nivolumab or ipilimumab or any of its excipients.

          -  Has had prior anticancer therapy within 4 weeks of study Day 1 or has not recovered
             (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more
             than 4 weeks earlier.

          -  Has a known additional malignancy that is progressing or requires active treatment.

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment. Patients with allografts (including liver transplants) are
             not eligible for this protocol.

          -  Has known history of, or any evidence of active, non-infectious pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the screening visit through 120 days
             after the last dose of trial treatment.

          -  Has received a live vaccine within 30 days of planned start of study therapy.

          -  Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
             and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with adverse events
Time Frame:3 years
Safety Issue:
Description:To determine the safety and tolerability of SBRT followed by nivolumab or ipilimumab with nivolumab for hepatocellular carcinoma by establishing the rates of toxicity that occur within 6 months from start of SBRT by analyzing the number of patients with adverse events.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:3 years
Safety Issue:
Description:Estimate the investigator determined best overall response rate.
Measure:Number of long-term adverse events
Time Frame:from date of randomization until the date of last documented adverse event or date of death from any cause, whichever comes first, up to 100 months
Safety Issue:
Description:Estimate the rates of long-term adverse events (after 6 months) from the end of SBRT.
Measure:Time to progression free survival
Time Frame:from date of randomization until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months
Safety Issue:
Description:
Measure:Time of overall survival
Time Frame:from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Safety Issue:
Description:
Measure:Rate of disease control
Time Frame:from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Safety Issue:
Description:
Measure:Rate of local control of the SBRT treated lesion
Time Frame:from date of randomization until the date of death from any cause, whichever comes first, up to 100 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

Trial Keywords

  • hepatocellular carcinoma
  • nivolumab
  • ipilimumab
  • stereotactic body radiotherapy
  • SBRT

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